Production of 3,3-disubstituted {62 -lactams

ABSTRACT

Production of 3,3-disubstituted Beta -lactams by dehydrohalogenation of Beta -halocarboxylic amides in the presence of basic compounds at elevated temperature, and the new 3,3-disubstituted Beta -lactams themselves. The known and new compounds which can be prepared by the process according to the invention are valuable starting materials for the production of fibers, textile auxiliaries, pesticides and plastics.

United States Patent m Merger [451 Jan. 16, 1973 [541 PRODUCTION OF3,3-DISUBSTITUTED B-LACTAMS [75] Inventor: Frans Merger, Ludwigshafen',Germany 73 Assignee: Badisc'he Anilin- & Soda-Fabrik Akas fil flhici Lievzissbi snll hine, Germany [22] Filed: May 19, 1969 [21] Appl. No.:825,931

[56] References Cited UNITED STATES PATENTS 3,297,754 1/1967 Bantjes2607239 OTHER PUBLICATIONS Knunyants et a]., Chem. Abstracts, Vol. 55,Co ls.

18696-18697 (1961). Knunyants et al.,. Chem. Abstracts, Vol. 50, Co].11277 (I956).

Primary Examiner-Alton D. Rollins i Attorney-Johnston, Root, O'Keeffe,Keil, Thompson and Shurtleff v [57] ABSTRACT Production of I3,3-disubstituted B-lactams by dehydrohalo'genation of B-halocarboxylicamides in the presence of basic compounds atelevated temperatur'e, andthe new 3,3-disubstituted B-lactams themselves. The known and newcompounds which can be prepared by the process according to theinvention are valuable starting materials for the production of fibers,

- textile auxiliaries, pesticides and plastics.

4 Claims, No Drawings and each denotes PRODUCTION or 3,3-DISUB'STITUTED'p- LACTAMS The invention relates to the production of 3,3-disubvstituted B-lactams by dehydrohalogenation of B-haloamides in thepresence of basic compounds at elevated temperature, and new substancesof this type.

B-lactams (the internal cyclic amides of B-amino acids) cannot beprepared direct from the B-amino acids. The condensation of esters ofB-amino acids with Grignard compounds (Liebigs Annalen der Chemie,

614, 158 (1958)), and the condensation of B-amino acids with phosphoruspentachloride in the presence of acetyl chloride (British Pat.specification Nos. 829,663

.dehydrobromination of appropriate B-bromoamides with sodamide in liquidammonia and particularly B- aryl-B-propionarylamides with potassium,sodium or lithium hydroxide or Triton B at C in aliphatic ketones assolvent. Similarly, the cyclization of madiphenyl-fi-bromoamides bymeans of sodium ethylate, sodium isopropylate and the said hydroxides inethanol into 3,3-diphenylacetidinones is also mentioned. This methodcannot however be applied with good results to other a,a-disubstitutedB-bromoamides (Liebigs Anacidity of the basic compounds being less thanor equal to that of tertiary alcohols (column 3, line 45) in polarsolvents. Reaction of B-bromopivaloylamide to form pivalolactam does nottake place in the presence of lithium carbonate and dimethylformamide(Table 1,

' Example 8).

It is an object of this invention to provide a new process fortheproduction of 3,3-disubstituted B-lactams in a simpler manner, in goodyields and in high purity.

Another object of this invention is the new 3,3-disubstituted B-lactams.

These and other objects are achieved and 3,3-disubstituted B-lactamshaving the general formula:

in which R, R, R and R may be identical or different an aliphatic,cycloaliphatic, araliphatic or aromatic radical, R and/or R may alsodenote a hydrogen atom, R and R together with the adjacent carbon atommay also form a cycloaliphatic ring, are advantageously obtained bydehydrohalogenation of B-haloamides in the presence of basic compoundsat elevated temperature, when a B-haloamide having the general formula:

li li ii III' in which R, R R and R have the meanings given above and Xdenotes a halogen atom, is dehydrohalogenated in he presence of a basiccompound of a metal of main groups 1, 2 or 3 or subgroups 1, 2, 3, 4, 7or 8, which has a higher acidity than tertiary butanol, at a temperatureof from 100 to 450 C.

When bromopivaloyl-N-methylamide is used, the reaction may berepresented by the following equation:

As compared with prior art methods, the process according to theinvention gives a large number of 3,3- disubstituted B-lactams in asimpler way and in some cases in better yields and higher purity. Havingregard to the state of the art, it is surprising that these advantageousresults are achieved using the said catalysts and in the temperaturerange of the process according to this invention.

The starting materials used are B-haloamides having the general formula(11) which can readily be prepared by reaction of B-halocarboxylicchlorides with ammonia or amines. Preferred starting materials (11) andconsequently preferred end products (I) are those in whose formulae R,R, R and R may be identical or different and each denotes an alkyl,cycloalkyl, aralkyl or aryl radical in each case having up to ten,particularly up to seven, carbon atoms, R and/or R may be a hydrogenatom, R and R together with the adjacent carbon atom may form acycloaliphatic ring, preferably having five or siie ring members, and Xdenotes a chlorine or bromine atom. The said radicals may also bear assubstituents groups and/or atoms which are inert under the reactionconditions, for example chlorine or bromine atoms as substituents of anaryl radical, nitro groups, alkyl groups having one to six carbon atoms.Preferred end products (I) are in particular the new3,3-dimethylazetidinones-(2) bearing as a substituent a phenyl radicalin the l-position which may bear one or more halogen atom assubstituents, and the end products specified in Examples 10 to 15.Preferably the phenyl radical in the 1-position is unsubstituted or maybear one or two chlorine atoms and/or bromine atoms as substituents.When B-haloamides which bear no substituents on the nitrogen atom areused, varying amounts of corresponding B-hydroxycarboxylic nitriles maybe formed in addition to the end adimethyl-B-bromopropionic acid N-(4-chlorophenyl)amide, a-dimethyl-Bbromopropionic acid N-3 ,4-

(dichlorophenyl)-amide, a-dimethyl-B-bromopropionic acidN-(4-nitrophenyl)-amide, a,a-dimethyl-B-bromobutyric acid N-phenylamide,a,a-dibenzyl-B-bromopropionamide,a,a-dimethyl-B-bromo-B-phenylpropionamide The reaction is carried out inhe presence of basic compounds of metals of main groups 1, 2 and 3 orsubgroups 1, 2, 3,4, 7 or 8 with substances having a higher acidity thanthat of tertiary butanol, or mixtures thereof. Preferred basic compoundsare the carbonates, bicarbonates, oxides, hydroxides, alcoholates andsalts of organic acids, particularly of aliphatic acids, for exampleformates, acetates, of the abovementioned metals. Examples of suitablemetals are lithium, sodium, potassium, copper, silver, calcium,strontium, barium, mercury, lead, iron, cobalt and nickel. It ispreferred to use lithium carbonate, sodium carbonate, potassiumcarbonate, barium carbonate, the analogous bicarbonatesor lead oxide.The basic compound is as a rule used in an amount of from 50 to 200percent by weight with reference to starting material (11).

The reaction is carried out at a temperature of from 100 to 450 C,particularly from 160 to 350 C, preferably from 160 to 250 C,atmospheric pressure or preferably at subatmospheric pressure,continuously or batchwise. As a rule a solvent is not used, particularlynot a polar solvent. High boiling inert heat exchange media, for exampleparaffin oil or phthalic esters, may be used if desired, generally in anamount of from 100 to 300 percent by weight with reference to startingmaterial (ll).

The reaction may be carried out as follows:

The starting material and the basic compound are kept v method, forexample by recrystallization of fractional distillation. Fractionaldistillation is recommended particularly for the separation of the endproduct from considerable amounts of nitrile as byproduct.

The reaction may also becarried out in the presence of one of the saidheat exchange media with good mixing. A mixture of the basic compoundand the heat exchange medium may also be brought to the reactiontemperature followed by the addition to the mixture of the startingmaterial (ll), if desired in the form of a melt, at a rate correspondingto the amount of end product being distilled off per unit time. It isalso possible tobring a mixture of the starting material (11) and theheat carrier to the reaction temperature and then to add the basiccompound in an appropriate manner, for example with a metering screw.

The known and new compounds which can be I prepared by the processaccording to the invention are v C 0 1750) and 9 parts of valuablestarting materials for the production of fibers, textile auxiliaries,pesticides and plastics. Reference is made to the said patentspecifications and literature for details concerning their use.

The following Examplesillustrate the invention. The parts specified inthe Examples are parts by weight.

EXAMPLE 1 A suspension of 150 parts of. lithium carbonate in. 200 partsby volume of paraffin oil is heated to 200 C in a stirred vessel.One-hundred eighty parts of molten bromopivaloylamide is added in thecourse of 2 hours from a reservoir kept at 1 10 "C, while stirringvigorously, and the end product is distilled off at the same time at mmHg into an ice-cooled receiver. After a total duration of 3 hours, thebottoms temperatu're being gradually increased to 250 C, distillation isover. The crude end product is subjected to fractional distillation and52.2 parts of pivalolactam (equivalent to 55.4 percent of the theory)having a boiling point'of 109 C at 20 mm Hg (n,, 1.4487; infraredspectrum:

starting material are obtained.

EXAMPLE 2 A suspension of 250 parts of anhydrous sodium carbonate in 200parts by volume of paraffin oil is heated to to C in a stirred vessel.While stirring vigorously, parts of bromopivaloylamide is allowed toflow in in the course of 2 hours and the product is distilled offsimultaneously at 50 to 80 mm Hg into an ice-cooled receiver. The crudeproduct is fractionally distilled and in the boiling range from 95 to 99C at 13 mm Hg a mixture is obtained which consists of 32.2 parts(equivalent to 34.6 percent of the theory) of pivalolactam and 52.4parts of hydroxypivalonitrile having a refractive index n,, 1.4380 and 11 parts of starting material. Pivalolactam can be separated by renewedfractional distillation from the mixture at a boiling point of 109 C at20 mm Hg.

EXAMPLE 3 One-hundred eighty parts of bromopivaloxylarnide isdehydrobrominated with 200 parts of sodium hydrogen carbonate in 200parts of paraffin oil as described in Example 2. 27.2 parts ofpivalolactam (equivalent to 29.5 percent of the theory), 48.3 parts ofhydroxypivalonitrile and 13 parts of starting material are obtained.

EXAMPLE 4 The distillate which passes over analogously to Example 1gives when fractionally distilled 7 parts of starting material, 3.4parts of pivalolactam and 5.1 parts of hydroxypivalonitrile.

EXAMPLE 5 100 parts of bromopivaloyl-N-methylamide (melting point 38 to40 C, prepared from bromopivaloyl chloride and methylamine) is mixedwell with 100 parts of sodium carbonate by grinding and heated at 80 mmHg in distillation apparatus rapidly to 120 C and gradually in thecourse of another 90 minutes to 240 C.'A distillate is thus obtainedhaving a boiling point of from 80 to 110 C. Renewed fractionaldistillation gives 6.5 parts of starting material and 39 parts ofl,3,3-trimethylaztidinone-(2) (equivalent to 71.5 percent of the theory)at a boiling point of 63 to 64 C at 12 mm Hg.

EXAMPLE 6 200 parts of bromopivaloyl-N-phenylamide (melting point 74 to75 C, prepared from bromopivaloyl chloride and aniline) is well mixedwith 250 parts of sodium carbonate and heated at from 2 to 3 mm Hgrapidly to 120 C and gradually in the course of another 2 hours to 250C. The distillate which passes over at from 50 to 154 C gives whenfractionally distilled 12 parts of starting material and 114.3 parts ofl-phenyl- 3,3-dimethylazetidinone-(2) (equivalent to 89 percent of-thetheory) having a boiling point of 1 15 to 1 16 C at 2 mm Hg.

Analysis: found: C 75.2%; H 7.5%; N 7.7%; O 8.9% calculated: C 75.40%; H7.48%; N 7.99%; O 9.13%.

EXAMPLE 7 Two hundred parts of bromopivaloyl-N-(4- chlorophenyl)-amide(melting point 84 to 85 C, boiling point 186 to 188 C at 1 mm Hg,prepared from bromopivaloyl chloride and 4-chloroaniline) and 200 partsof sodium carbonate are rapidly heated at mm Hg to 160 C and graduallyin the course of another 2 1 hours to 350 C. The distillate passing overat from 75 to 195 C gives when fractionally distilled 11 parts ofstarting material and 94.9 parts of l-(4-chlorophenyl)- EXAMPLE 8 Onehundred and ten parts of bromopivaloyl-N-(3,4- dichlorophenyl)-amide(melting point 1 19 to 120 C,

prepared from bromopivaloyl chloride and 3,4-

dichloroaniline) and 100 parts of sodium carbonate are rapidly heated at1 mm Hg to 200 C and gradually in the course of another 90 minutes to320 C. The distillate passing over at from 150 to 170 C gives wheni'ractionally distilled 4 parts of starting material and 38.2 parts ofl-(3,4-dichloropheny1)-3,3-

dimethylazetidinone (equivalent to 48 percent'of the theory) having aboiling point of 136 to 138 Cat 1 mm Hg and a melting point of from 60to 62 C. 1nfrared spectrum: CO 1750 cm.

Analysis:

found: C 54.2%; H 4.5%; N 5.7%; O 6.8%; CI 29.1% calculated: C 54.12%; H4.54%; N 5.74%; O 6.55%;

EXAMPLE 9 parts of 2-methyl-2-phenyl-3-bromopropionyl- N-methylamide(melting point 96 to 98 C, prepared frommethyl-2-phenyl-3-bromopropionyl chloride and methylamine) and parts ofsodium carbonate are heated rapidly at 3 mm Hg to C and in the course ofanother 90 minutes to 250 C. The distillate passing over at from 60 to Cgives when fractionally distilled 3.6 parts of starting material and43.7 parts of 1-methyl-3-methyl-3-phenylazetidinone-(2) (equivalent to66.2 percent of the theory) having a boiling point offrom 113 to 114 Cat 1 mm Hg.

EXAMPLES 10 to 15 The following reactions are carried out analogously toExample 8 using 2.5 moles of sodium carbonate per mole of startingmaterial: m. point melting point in p-phenylenediamide lclaim: l. Aprocess for the production of 3,3-disubstituted 260-263(3,3-dimethylazetidinon) fi-lactams having the formula:

in which R, R, R and R may be identical or different and each denotes analkyl, cycloalkyl, aralkyl or aryl radicalin each case having up to tencarbon atoms, R"

and/or R may be a hydrogen atom and R and R together may betetramethylene or pentamethylene, by dehydrohalogenation of aB-haloamide in the presence of a basic compound at elevated temperature;wherein a B-haloamide having the formula:

in which R, R R and R have the above meanings and X denotes a halogenatom is dehydrohalogenated in the presence of a basic compound selectedfrom the group consisting of carbonates and bicarbonates of lithium,sodium, potassium an d barium in an amount of 50 to 200 percentby'weight with reference to said [3- 3. A process as claimed in claim 1wherein said reac-v tion temperature is in the range of 160 to 250? C.

4. A process as'claimed in claim I wherein said reaction is carried outin the presence of a high boiling,

inert heat'ex'changemedium in an amount of 100 to 300 percent by weightwith reference to said B-haloamide. v

2. A process as claimed in claim 1 wherein said reaction temperature isin the range of 160* to 350* C.
 3. A process as claimed in claim 1wherein said reaction temperature is in the range of 160* to 250* C. 4.A process as claimed in claim 1 wherein said reaction is carried out inthe presence of a high boiling, inert heat exchange medium in an amountof 100 to 300 percent by weight with reference to said Beta -haloamide.